Food restriction is the only manipulation known to retard mammalian aging processes. It is our premise that understanding the mechanisms by which food restriction modulates the aging processes will provide insights on the primary nature of those processes as well as a data base that will be invaluable in seeking the meaningful intervention of human aging. We have explored the major hypotheses (retardation of growth and development, reduction of fat mass, reduction of metabolic rate) that have been proposed and found them not to be valid. Our research has also shown that food restriction does not influence the aging processes by reducing the intake of calories or other nutrients per unit metabolic mass. This has led to the following general hypothesis: the reduction of total nutrient input per rat rather than per unit metabolic mass is coupled to the aging process by endocrinologic or intermediary metabolic or endocrine-metabolic events. In this proposal, the basic groundwork in regard to this general hypothesis will be sought through the following eight projects: Project I will explore the potential roles of the glucocorticoid and the glucose-insulin systems as couplers of food restriction to the aging processes; Project II will explore the sympathetic nervous system, the thyroid gland and their interaction as potential couplers of food restriction to the aging processes; Project III will utilize the thyroidal C cell endocrine system as a model for exploring the cellular and molecular mechanisms by which food restriction modulates aging processes; Project IV will study protein turnover as a mechanism by which food restriction modulates the aging processes; Project V will investigate free radical-promoted lipid peroxidation as an aging process and its modulation by food restriction; Project VI will explore the roles of total rat energy metabolism and of physical activity in the retardation of the aging processes; Project VII will explore the immune system as a tool for uncovering the molecular, cellular, metabolic and endocrine bases of the action of food restriction on the aging processes; Project VIII will supply the rats required by the other projects, will execute longevity studies related to these projects and will extend the findings of our current study in regard to dietary protein and age-related renal disease.